SUN-753 - Evolving Musculoskeletal Challenges in Silver-Russell Syndrome: A Case Study

Introduction: Silver-Russell syndrome (SRS) is a rare imprinting disorder that most often presents with prenatal and postnatal growth retardation, body asymmetry, relative macrocephaly, a prominent forehead, feeding difficulties, hypoglycemia, and low muscle mass. Genetic mechanisms are detectable in about 60% of cases, with diagnosis often resting on clinical criteria. The most common etiologies are loss of methylation (LOM) at chromosome 11p15.5 (30%-60% of cases) and maternal uniparental disomy of chromosome 7 (mUPD7) (~10%). While various clinical features of SRS have been well characterized, osteoporosis is a rare and infrequently reported finding.

Case: A 21-year-old individual with a history of myoclonus dystonia (DYT11-related) and significant motor delays in infancy was diagnosed with SRS after detection of abnormal mUPD7 and muscle biopsy showing complex VI deficiency. The patient’s course was complicated by ankylosing spondylitis and childhood-onset growth hormone deficiency (treated from ages 5–9). For ankylosing spondylitis, the patient received monoclonal antibodies and intermittent steroids. After a fall, a Dual-energy X-ray Absorptiometry scan (DXA) revealed low bone density (lumbar spine Z-score -2.0; left hip -1.8), and a computed tomography (CT) showed a T11 wedge deformity, meeting clinical criteria for osteoporosis. Osteoporosis was attributed to consequences of SRS, including reduced muscle mass, limb length discrepancy, altered bone remodeling, and additional risk from chronic illness and steroid use. Treatment with Evenity was initiated.

Discussion: SRS due to mUPD7 typically presents with an endocrine profile similar to nonsyndromic small-for-gestational-age individuals, with main musculoskeletal effects resulting from decreased IGF-2 expression. Resistance to IGF-1, seen in the LOM variant, further impairs muscle growth. In this case, osteoporosis likely resulted from a combination of reduced muscle mass, body asymmetry, limb length discrepancy, childhood growth hormone deficiency, chronic inflammatory disease, intermittent steroid use, and abnormal mechanical loading. DXA can underestimate bone density in short-stature patients, but this individual met clinical osteoporosis criteria. Early growth hormone therapy helps not only with height but also with muscle mass and mobility. Endocrine complications in SRS may include hypoglycemia, premature adrenarche, and insulin resistance. Weight-bearing exercise, vitamin D, and calcium are important preventive measures.

Conclusion: Multifactorial bone fragility in SRS requires comprehensive management with endocrine optimization, weight-bearing exercise, and nutritional supplementation. This case underscores the importance of lifelong multidisciplinary monitoring to address the evolving musculoskeletal and metabolic complications of the syndrome.

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